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A5874 - Reliability of Inspiratory Flow Reserve (IFR) Endpoints and Robustness of Longitudinal Analyses Assessing the Effect of Idebenone on IFR in Patients with Duchenne Muscular Dystrophy (DMD)
Author Block: J. Karafilidis1, H. Mayer2, M. Leinonen3, G. Buyse4; 1VP, Medical Affairs, Santhera Pharmaceuticals USA, Burlington, MA, United States, 2Childrens Hosp of Philadelphia, Philadelphia, PA, United States, 3Consultant, Santhera Pharmaceuticals, Liestal, Switzerland, 4University Hospitals Leuven, Leuven, Belgium.

Background:
In addition to commonly used expiratory respiratory function endpoints, peak expiratory flow (PEF), forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1), inspiratory flow reserve (IFR) was assessed in the DELOS study1. Previous analyses showed a significant treatment effect of idebenone compared with placebo for expiratory function endpoint (PEF, which was the primary endpoint)1 and for parameters assessing dynamic inspiratory function2.
Methods:
The objective of this analysis is to assess the reliability and robustness of dynamic inspiratory function measures. In the DELOS study, 64 DMD patients, 10-18 years, not using concomitant glucocorticoids who were in respiratory function decline phase were randomized to idebenone or placebo for 52 weeks. The inspiratory flow reserve (IFR) is the ratio between the largest inspiratory flow during tidal breathing (V'I,max(t)) and the highest flow during an inspiratory FVC maneuver (V'I,max(FVC)), as [1-V'I,max(t)/V'I,max(FVC)] x 100%. A series of 3 to 5 consecutive maneuvers were performed at each visit. For the primary definition, the lowest V'I,max(t) and highest V'I,max(FVC) of these maneuvers were used2. Sensitivity analyses were performed with 4 alternative definitions. The reliability of IFR endpoints was assessed with intra-individual co-efficient of variation (CV) between the screening and baseline visits. Treatment differences between idebenone and placebo at Week 52 were estimated with Mixed Model for Repeated Measures.
Results:
The CV of the primary definition of IFR was 14.4%. The CVs of the alternative endpoint definitions ranged between 17.6% - 25.7%. The difference in change from baseline to Week 52 between idebenone and placebo groups was 5.78% [95% CI: 0.28 - 11.27; p=0.040]. Comparable differences between idebenone and placebo were seen with the alternative endpoint definitions, with p-values ranging between 0.013 and 0.113.
Conclusion:
When comparing the CVs presented here with previous reports3, IFR is less reliable than the conventional expiratory respiratory function endpoints (PEF, FVC, FEV1) but more reliable than the widely used maximal inspiratory and expiratory pressure measurements (MIP, MEP) in DMD patients who are in respiratory function decline. The definition of IFR using the lowest V'I,max(t) and highest V'I,max(FVC) from 3-5 consecutive maneuvers lead to lowest CV. The treatment effect of idebenone compared with placebo on dynamic inspiratory function was consistent regardless of the method of endpoint definition and supported efficacy of idebenone treatment shown for expiratory function outcomes1.
References:
1Buyse GM et al. Lancet 2015;385:1748-57.
2Buyse GM et al. Pediatr Pulmonol. 2017;52(4):508-515.
3Meier T et al. Neuromuscul Disord. 2017;27(4):307-314